Phosphatases, as therapeutic targets, offer a largely underexplored opportunity for the discovery of novel drugs and expansion of the current state of the art in medicinal chemistry. In recent years, the protein tyrosine phosphatase 4A family (PTP4A1, PTP4A2, and PTP4A3) has garnered much interest and ample validation as an anticancer target. All three phosphatases are ˜20 kD and possess a unique C-terminal prenylation motif important for association with the plasma membrane and early endosomes. There is no established substrate for any PTP4A family member.
Compared to other phosphatases, PTP4A3 has a higher rate of overexpression in many cancer cell lines, especially in colorectal cancer, potentially allowing for a more selective inhibition by drug molecules. Elevated levels of PTP4A3 mRNA were first observed in metastatic colorectal cancer and is associated with late stage metastatic disease.
Other human cancers express high PTP4A3 levels including, but not restricted to tumors of the breast, ovary, cervix, lung, brain, prostate, liver, stomach, and stroma and to leukemias and lymphomas. Elevated PTP4A3 expression often correlates with increased tumor invasiveness and poor prognosis and ectopic PTP4A3 overexpression enhances tumor cell migration and invasion in vitro. PTP4A3 also has been proposed to have a role in the progression of cardiac hypertrophy by inhibiting intracellular calcium mobilization in response to angiotensin II.
There is a long felt need in the art for compositions and methods useful for inhibiting protein tyrosine phosphatases and for treating diseases and disorders. The present invention satisfies these needs.